Sign up to receive free email alerts when patent applications with chosen keywords are publishedSIGN UP

Abstract:

Disclosed herein compositions including povidone-iodine (PVP-I) useful in
the treatment of acute and chronic bacterial, viral and fungal infections
of the internal, middle and external ear of mammals, including humans.

Claims:

1. A method of treating a mammal having an otic infection, the method
comprising contacting the ear of the mammal with a composition
comprising:a. povidone iodine (PVP-I) at a concentration of 0.01%-5.0%;
andb. a steroid at a concentration of 0.01%-2.0%.

2. The method of claim 1, wherein the otic condition is at least one
member selected from the group consisting of bacterial otitis externa,
malignant otitis, fungal otitis externa, otomycosis, otitis media, and
otitis interna.

3. The method of claim 1, wherein the steroid is selected from the group
consisting of a dexamethasone, a fluoromethalone, a lotoprendol, a
medrysone, a prednisolone, a difluprednate, a rimexolone, and a
hydrocortisone.

4. The method of claim 1, wherein the steroid is dexamethasone or a salt
thereof.

5. The method of claim 1, wherein the composition is contacted to the ear
in the form of an ear drop or a zinc acetate composition.

6. The method of claim 1, wherein the PVP-I is present at a concentration
of 1.0%-3.0%.

7. The method of claim 1, wherein the PVP-I is present at a concentration
of 2.0%.

8. The method of claim 1, wherein the steroid is present at a
concentration of 0.05%-0.1%.

9. The method of claim 1, wherein the steroid is present at a
concentration of 0.1%.

Description:

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001]This application is a continuation-in-part application of
PCT/2009/000563, filed on Jan. 28, 2009, which claims priority to U.S.
Provisional Patent Application No. 61/006,687, filed on Jan. 28, 2008,
both of which are incorporated by reference herein in their entirety.

BACKGROUND

[0002]Otitis externa (external ear infection) is an inflammation of the
outer ear and ear canal. It is a common cause of earache in humans and a
common problem in dogs, cats and other mammals. It also occurs in many
other species. This disorder involves inflammation of the skin of the ear
canal. The inflammation can be caused by active fungal, viral or
bacterial organisms. The ear canal skin often swells and may become
painful and tender to touch.

[0003]Otitis media (middle ear infection) occurs in the area between the
ear drum and the inner ear, including the Eustachian tube. Otitis media
is very common in childhood, with the average toddler experiencing two to
three episodes a year, almost always accompanied by a viral upper
respiratory infection (URI), mostly the common cold. The rhinoviruses and
adenoviruses that cause many common cold symptoms cause swelling and
congestion in the inner ear which can permanently damage middle ear
structures. Otitis media is also frequently caused by a variety of
bacteria and other viruses.

[0004]Furthermore, ear infection (particularly in children) is one of the
many diseases that have become hard to treat with traditional antibiotic
drugs because of antibiotic resistant bacteria and antibiotic-resistant
microorganisms. Most cases of otitis media, for example, are caused by
one of several major pathogens, Streptococcus pneumonia, Haemophilus
influenza, Moraxella catarrhalia, Staphylococcus aureus, Staphylococcus
epidermidis, or Pseudomonas aeruginosa. There is thus an urgent need to
develop new, non-antibiotic approaches to prevent and manage these
diseases.

BRIEF SUMMARY OF THE INVENTION

[0005]The invention includes a method of treating a mammal having an otic
infection, the method comprising contacting the ear of the mammal with a
composition comprising povidone iodine (PVP-I) at a concentration of
0.01%-5.0% and a steroid at a concentration of 0.01%-2.0%.

[0006]In an aspect, the otic condition is at least one member selected
from the group consisting of bacterial otitis externa, malignant otitis,
fungal otitis externa, otomycosis, otitis media, and otitis interna. In
an aspect, the PVP-I is present at a concentration of 1.0%-3.0%. In
another aspect, the PVP-I is present at a concentration of 2.0%.

[0007]In an aspect, the steroid is selected from the group consisting of a
dexamethasone, a fluoromethalone, a lotoprendol, a medrysone, a
prednisolone, a difluprednate, a rimexolone, and a hydrocortisone. In
another aspect, the steroid is dexamethasone or a salt thereof. In an
aspect, the steroid is present at a concentration of 0.05%-0.1%. In
another aspect, the steroid is present at a concentration of 0.1%.

[0008]In an aspect, the composition is contacted to the ear in the form of
an ear drop, a zinc acetate composition, or an acetic acid composition.

DETAILED DESCRIPTION OF THE INVENTION

[0009]For the treatment of otic infections, there are currently no
effective antifungals, no effective antivirals and only one antibacterial
available combined in the same dose form with anti-inflammatories. It is
well known that more dilute concentrations of PVP-I exhibit a more potent
antimicrobial effect in vitro, however previous attempts to produce a
clinically effective dilute PVP-I otic solution have been so far
unsuccessful. It is further noted that the formulation of PVP-I with
other active ingredients can be complicated by reactivity of iodine
species with other labile chemical moieties. Such reactive species are
common on many steroids and non-steroidal anti-inflammatories.

DEFINITIONS

[0010]As used herein, "ear" refers to the biological structures
responsible for hearing and equilibrium in vertebrates, among other
things. "Ear" also include the visible portions of the biological
structures, such as those often present on mammals.

[0011]The term "otic" refers to the ear, in general.

[0012]The term "treating", as used herein, refers to a detectable
improvement in an adverse condition and/or a lessening the symptoms of
the condition upon contacting a mammal with an oral composition of the
invention and/or according to a method of the invention. The term
"treating" encompasses both a partial improvement in an adverse condition
and a complete eradication (i.e., "cure") of the condition. In an aspect,
an infection is treated. In another aspect, inflammation is treated. In
another aspect, infection and inflammation are both treated.

Treatment of Otic Infections

[0013]Cleaning in and around the ear canal, as well as treating otic
infections, can sometimes be complicated by a buildup of cerumen, dead
skin and other organic matter in and around the ear canal. Iodine is
known to react with such substances, as iodine is chemically reactive,
and active as a reducing agent. It is known, for example, that such
substances in and around the ear canal can deplete the concentration of
iodine in a 10% iodine solution that is used for such cleaning purposes,
thereby depleting the cleaning and antimicrobial effectiveness of the
iodine solution.

[0014]As disclosed herein, it has been surprisingly found that
compositions comprising povidone-iodine and a steroid are advantageously
effective as antimicrobial agents for otic indications. Additionally, it
has been found that the inventive compositions are effective at lower
concentrations of iodine than shown and/or used in the prior art.

[0015]It has now been determined that the compositions and formulations
disclosed herein are surprisingly tolerable in the human ear. It is also
disclosed herein that formulations of the invention have in vitro
activity against many common bacterial, viral and fungal pathogens. In an
aspect, the invention encompasses treatment of a mammalian ear. In an
aspect, the mammal is a human.

[0016]In an embodiment, a condition treatable with a composition of the
invention includes, but is not limited to, bacterial otitis externa,
malignant otitis, fungal otitis externa, otomycosis, otitis media, and
otitis interna.

Antimicrobials--Povidone Iodine

[0017]In one embodiment, it is desirable to treat otic disorders as
disclosed herein with both anti-inflammatories and antimicrobials
suitable for the casuative organisms. Povidone iodine is an antimicrobial
useful in the present invention.

[0018]Povidone-iodine (PVP-I) is a water-soluble complex of iodine with
polyvinylpyrrolidone (PVP), with from 9.0% to 12.0% available iodine,
calculated on a dry basis. PVP-I can be further formulated into topical
antiseptic products as a solution (with surfactants and/or alcohol),
aerosol or ointment at concentrations from 7.5% to 10%. These products
are sold over-the-counter (OTC) and used in hospitals for cleansing and
disinfecting the skin, preparing the skin preoperatively and treating
infections susceptible to iodine. It is believed that the membrane
proteins in the cell architecture are oxidized and subsequently denatured
by free iodine generated from PVP-I solutions. This then leads to the
disruption of cellular boundaries and the free passage of iodine into the
cell.

[0019]Concentrations of PVP-1 up to 10.0% (w/w, aqueous) are known to be
safe for use in the external ear and similarly safe if exposed to the
inner ear through a ruptured tympanic membrane.

PVP-I+Steroid Compositions

[0020]In one embodiment, a stable, tolerable formulation of PVP-I with
steroids has been developed, as set forth in U.S. Patent Application
Publication No. 2007/0219170, incorporated herein by reference in its
entirety. PVP-I and steroids are prepared in aqueous solution with common
pharmaceutical excipients that is surprisingly stable at room temperature
and elevated temperature in glass bottles and high-density polyurethane
(HDPE) plastic bottles.

[0021]The affinity of free iodine for reaction with --OH, --SH and --NH
functional groups is well described in the literature and forms the basis
for the anti-microbial activity of iodine-containing solutions (Rackur H.
J. Hosp. Infect., 1985; 6: 13-23, and references therein). Dexamethasone
(9-Fluoro-11βα, 17,
21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione) contains three
such moieties (--OH) at the 11, 17 and 21 positions and two double bonds.
One of skill in the art will understand that these hydroxyl groups would
be prone to covalent substitution reactions by the free iodine generated
in the solution equilibrium reaction described above for PVP-I, and the
double bonds would be prone to electrophilic iodination reactions.

[0023]In an embodiment, as set forth in U.S. patent application Ser. No.
11/636,293, incorporated herein by reference in its entirety as U.S.
Patent Application Publication No. 2007/0219170, various solutions of
PVP-I and dexamethasone remain stable for many months, when prepared
according to the compositions disclosed therein. Based on the stability
data disclosed, such compositions may be stable for years. The reaction
of dexamethasone and PVP-I does not proceed to any appreciable extent at
room temperature, in light or dark, or over time. After 8 weeks, the
available iodine in the combination (0.3% PVP-I starting concentration)
decreased by 20%.

[0024]Previously, for a dexamethasone/PVP-I composition, the available
iodine of a 0.625% PVP-I solution was determined to be 91% at 25°
C. and 98% at 4° C. after 5 weeks storage, respectively. (Iryo
Yakugaku 2003, 29(1), 62-65). Dexamethasone/PVP-I compositions set forth
herein showed demonstrated a stabilized dilute PVP-I solution. After 8
weeks at room temperature, the available iodine in solutions with 0.5%
and 1% PVP-I were over 99%.

[0026]The compositions are useful in the treatment of active infections
from bacterial, mycobacterial, viral, fungal, or amoeba causes, as well
as treatment to prevent such infections in appropriate clinical settings.
In an embodiment, the invention provides a PVP-I+steroid composition that
is non-reactive and stable, i.e., the PVP-I and the steroid are
compatible. In an aspect, the steroid is dexamethasone.

PVP-I+Non-Steroidal Anti-Inflammatory Compounds

[0027]It was also shown that PVP-I reacted with Ketorolac (a non-steroidal
anti-inflammatory) rapidly and that the Ketorolac was completely consumed
and the available iodine in the PVP-I complex was reduced significantly
depending on the ratio between Ketorolac and PVP-I. The combination of
PVP-I and dexamethasone sodium phosphate also proved to be less stable,
but not overly reactive (some dissociation of PVP-I complex to an unknown
polymeric complex was observed in the UV spectra and the iodine
concentration was reduced approximately 5% after 12 weeks. It was further
observed that PVP-I reacts immediately with proparacaine and releases
free iodine rapidly.

[0029]In another aspect, the invention provides topical pharmaceutical
compositions for use in treating and relieving the symptoms of ear,
including, but not limited to, otitis interna, otitis media and otitis
externa (both acute and chronic). In an embodiment, the compositions
comprise PVP-I in an amount effective to reduce the growth of infection
causing microbes and a pharmaceutically acceptable carrier therefor. In
an embodiment, PVP-I is present in an otic composition in the range of
0.1%-10%. In an embodiment, the otic compositions may additionally
comprise a steroid, such as, but are not limited to, dexamethasone.

[0030]In compositions for topical administration, the mixtures are
preferably formulated as aqueous solutions at a pH of 3.5 to 6.5.
Preferably, the pH is adjusted to between 4 and 5. This pH range may be
achieved by the inclusion of suitable acids/bases in the composition.

[0031]In an aspect, a composition may comprise one or more of an
excipient, an antimicrobial agent, a preservative, a cosolvent, a
surfactant, a viscosity agent, and/or a bioadhesive agent, as set forth
in detail elsewhere herein.

[0032]In an aspect, a pharmaceutical preparation is a partially-alcoholic
preparation. As will be understood by the skilled artisan, inclusion of a
percentage of alcohol in the preparation will aid in the solubility of
the components, including the steroid and the PVP-I. The alcohol
component will also serve as a dehydrating component for the surface to
which the preparation is applied. Alcohols useful in the invention
include methanol, ethanol, and isopropanol, among others.

[0033]Lubricants

[0034]In an embodiment, a composition may comprise one or more lubricants
including, but are not limited to, propylene glycol, glycerin,
polyethylene glycol, dextran, blended polyvinyl alcohols, polyvinyl
alcohol, polyethylene glycol, light mineral oil, hydroxypropyl
methylcellulose, hypromellose, carbopol, carbomer 940 (polyacrylic acid),
polyvinyl pyrrolidone, white petrolatum, soy lecithin, and sodium
carboxyl methylcellulose, as well as other agents known to those skilled
in the art, or any combination thereof. Typically, such lubricants are
employed at a level of from 0.1% to 2% by weight. In an embodiment, the
lubricants are 1.0% Propylene glycol, 0.3% glycerin, 2.7% blended
polyvinyl alcohols, 1% polyvinyl alcohol, 1% polyethylene glycol, light
mineral oil, 0.3% hydroxypropyl methylcellulose, 1.0% soy lecithin, 0.25%
or 0.5% sodium carboxyl methylcellulose. In another embodiment, the total
weight of a PVP-I, artificial-tear based lubricant is between 0.1% and
4.5%.

[0042]Preservative agents include benzalkonium chloride, thimerosal,
chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, EDTA,
sorbic acid, Onamer M, other agents known to those skilled in the art, or
a combination thereof. Typically such preservatives are employed at a
level of from 0.001% to 1.0% by weight of final composition.

[0043]Co-Solvents

[0044]The compositions of the invention may contain one or more optional
co-solvents. The solubility of the components of the present compositions
may be enhanced by a surfactant or other appropriate co-solvent in the
composition. Such cosolvents/surfactants include polysorbate 20, 60, and
80, polyoxyethylene/polyoxypropylene surfactants (e.g. Pluronic F-68,
F-84 and P-103), cyclodextrin, tyloxapol, other agents known to those
skilled in the art, or a combination thereof. Typically such co-solvents
are employed at a level of from 0.01% to 2% by weight of the final
composition.

[0045]Soothing Agents

[0046]Furthermore, the compositions may comprise an effective amount of a
chemical agent to provide a cooling sensation to relieve mild otic
irritation, enhance comfort, provide a refreshing effect, and improved
sensation, when the PVP-I solution is applied to the ear. Such an agent
encompasses various chemicals and chemical classes, including, but are
not limited to, cooling agents such as menthol, menthol derivatives
including methone glycerin acetyl and menthyl esters, carboxamides,
menthane glycerol ketals, alkyl substituted ureas, sulfonamides, terpene
analogs, furanones, and phosphine oxides; or camphor, and borneol.

[0047]Viscosity Agents

[0048]The compositions of the invention may contain an optional viscosity
agent--that is, an agent that can increase viscosity. Viscosity increased
above that of simple aqueous solutions may be desirable to increase otic
absorption of the active compound, to decrease variability in dispensing
the formulation, to decrease physical separation of components of a
suspension or emulsion of the formulation and/or to otherwise improve the
otic formulation. Such viscosity builder agents include as examples
polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose,
carboxymethylcellulose, hydroxypropylcellulose, other agents known to
those skilled in the art, or a combination thereof. Such agents are
typically employed at a level of from 0.01% to 2% by weight of the final
composition.

[0049]Bioadhesive Agents

[0050]Bioadhesive agents can be used in the compositions to increase the
retention time of the drug gradient over the biological substrates. The
bioadhesive agents may include but are not limited to:
polyvinylpyrrolidone (PVP), xanthan gum, locust bean gum, acacia gum,
hydroxypropyl methylcellulose (HPMC), sodium alginate, pectin, gelatin,
carbomer, polyvinylalcohol, gellan gum, tragacanth, acacia, and sodium
carboxymethyl cellulose.

[0051]Formulations and Evaluation of Effectiveness

[0052]In an embodiment, methods and compositions of the invention can
reduce the progression of infectious otitis externa such that no
additional progression is detected. Any method can be used to determine
whether or not the severity of a symptom or the progression rate of
otitis externa is reduced. For example, a human having otitis externa can
be questioned regarding pain or discomfort before and after treatment to
determine whether a symptom of otitis externa (e.g., ear pain or ear
itching) is reduced. In some cases, a mammal can be observed or tested
for the severity of a symptom of otitis externa (e.g., ear discharge,
sensitivity of the ear to pressure, sensitivity of the earlobe to touch,
or reduced hearing) before and after treatment with an anti-infective
compound (e.g., PVP-I) and a steroid to determine whether or not the
severity of a symptom is reduced. In some cases, an otolaryngologist can
assess the severity of otitis externa (e.g., by performing a physical
examination and assigning a Grade 1 to 4 score, the characteristics of
which are known in the art) before and after treatment to determine
whether the severity of a symptom is reduced. To determine whether or not
progression of otitis externa is reduced, a physical examination can be
performed at different time points to determine the amount of erythema
and/or edema in and around the ear canal. The amount of erythema and
edema observed at different time points can be compared to assess the
progression rate. After treatment as described herein, the progression
rate can be determined again over another time interval to determine
whether or not the progression rate has decreased.

[0053]Therefore, it will be understood that an effective amount of a
composition comprising PVP-I and a steroid is any amount that reduces the
severity of a symptom or the progression of otitis externa without
producing significant toxicity to the mammal. For example, an effective
amount of PVP-I can be from about 0.1% to about 10% (e.g., about 2%)
povidone-iodine in an otic drop formulation. In an embodiment, an
effective amount of a steroid such as dexamethasone can be from about
0.05% to about 1.0% (e.g., about 0.1%) dexamethasone in an otic drop
formulation. In an embodiment, an effective amount of a composition
comprising PVP-I and dexamethasone can be from about 2 drops to about 8
drops of an otic drop formulation containing about 2% povidone-iodine and
about 0.10% dexamethasone applied to the ear.

[0054]In an aspect, an otic composition is a zinc acetate composition. In
another aspect, an otic composition is an acetic acid composition.

[0055]If a mammal does not appear respond to a particular amount of a
composition of the invention, then the amount of one or more of the PVP-I
and the dexamethasone, for example, can be increased. After receiving
this higher concentration, the mammal can be monitored for both
responsiveness to the treatment and toxicity symptoms, and adjustments
made accordingly. The effective amount can remain constant or can be
adjusted as a sliding scale or variable dose depending on the mammal's
response to treatment. Various factors can influence the actual effective
amount used for a particular application. For example, the frequency of
administration, duration of treatment, use of multiple treatment agents,
route of administration, immunocompetency of the mammal, and severity of
the otitis externa may require an increase or decrease in the actual
effective amount administered. The frequency of administration can be any
frequency that reduces the severity of a symptom or progression rate of
otitis externa without producing significant toxicity to the mammal. For
example, the frequency of administration can be from about once daily to
about four times daily (e.g., about twice daily). The frequency of
administration can remain constant or can be variable during the duration
of treatment.

[0056]In another aspect, a course of treatment with an anti-infective
compound and a steroid can include rest periods. For example, an
anti-infective and a steroid can be administered over a two week period
followed by a two week rest period, and such a regimen can be repeated
multiple times. As with the effective amount, various factors can
influence the actual frequency of administration used for a particular
application. For example, the effective amount, duration of treatment,
use of multiple treatment agents, route of administration,
immunocompetency of the mammal, and severity of the otitis externa may
require an increase or decrease in administration frequency. An effective
duration for administering a composition provided herein can be any
duration that reduces the severity of a symptom or the progression rate
of otitis externa without producing significant toxicity to the mammal.
Thus, the effective duration can vary from several days to several weeks,
months, or years. In general, the effective duration for the treatment of
otitis externa can range in duration from several days to several weeks.
In some cases, an effective duration can be for as long as an individual
mammal is alive. Multiple factors can influence the actual effective
duration used for a particular treatment. For example, an effective
duration can vary with the frequency of administration, effective amount,
use of multiple treatment agents, route of administration,
immunocompetency of the mammal, and severity of the otitis externa.

[0057]The above diagnosis and treatment considerations can be applied in a
similar manner to the treatment of otitis media and otitis interna.

[0075]1. Weigh out all powders and record weights [0076]2. Add 40% of
sterile water for injection to an appropriate size beaker. [0077]3. With
the aid of a homogenizer add the Dexamethasone and Tyloxapol. [0078]4.
Pour the above solution into a 100 ml serum vial with magnetic spin bar.
[0079]5. Use another 5% of water to rinse the beaker into the serum vial.
[0080]6. While spinning add Hydroxyethylcellulose, continue to spin until
uniform. [0081]7. Adjust pH of the above composition to 4.0. [0082]8. QS
to 50 ml. [0083]9. Crimp and Autoclave the container holding the above.
[0084]10. After autoclave cycle completely spin the contents until cool.
[0085]11. In a separate beaker add 40% of sterile water for injection
[0086]12. Add the following ingredients one by one in the following order
making sure each ingredient is completely dissolved before adding the
next: NaCl, EDTA, Sodium Sulfate, Povidone Iodine [0087]13. Adjust pH to
4.0. [0088]14. QS to 50 ml. [0089]15. Filter to sterilize the above.
[0090]16. Inject the filtered solution into the Autoclaved solution and
let spin until uniform. [0091]17. Dispense in amber glass bottles.

[0092]The invention has been described herein by reference to certain
preferred embodiments. However, as obvious variations thereon will become
apparent to those skilled in the art, the invention is not to be
considered as limited thereto. All patents, patent applications, and
references cited anywhere is hereby incorporated by reference in their
entirety.